Discovery of dual-activity small-molecule ligands of Pseudomonas aeruginosa LpxA and LpxD using SPR and X-ray crystallography
Autor: | Afroza Akhtar, Xueji Zhang, Sacco, Sophie E. Darch, Yu Chen, Kyle G. Kroeck, Logan D. Andrews, John E. Knox, D. Shoun, Frederick Cohen, Emmanuel W. Smith |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Models Molecular Stereochemistry Protein Conformation Allosteric regulation lcsh:Medicine Crystallography X-Ray Ligands Biochemistry Article 03 medical and health sciences Protein structure Bacterial Proteins Transferase lcsh:Science Magnesium ion Multidisciplinary 030102 biochemistry & molecular biology biology Chemistry Drug discovery lcsh:R Active site Surface Plasmon Resonance Ligand (biochemistry) Small molecule Chemical biology Acyl carrier protein 030104 developmental biology Pseudomonas aeruginosa biology.protein lcsh:Q Structural biology |
Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | The lipid A biosynthesis pathway is essential in Pseudomonas aeruginosa. LpxA and LpxD are the first and third enzymes in this pathway respectively, and are regarded as promising antibiotic targets. The unique structural similarities between these two enzymes make them suitable targets for dual-binding inhibitors, a characteristic that would decrease the likelihood of mutational resistance and increase cell-based activity. We report the discovery of multiple small molecule ligands that bind to P. aeruginosa LpxA and LpxD, including dual-binding ligands. Binding poses were determined for select compounds by X-ray crystallography. The new structures reveal a previously uncharacterized magnesium ion residing at the core of the LpxD trimer. In addition, ligand binding in the LpxD active site resulted in conformational changes in the distal C-terminal helix-bundle, which forms extensive contacts with acyl carrier protein (ACP) during catalysis. These ligand-dependent conformational changes suggest a potential allosteric influence of reaction intermediates on ACP binding, and vice versa. Taken together, the novel small molecule ligands and their crystal structures provide new chemical scaffolds for ligand discovery targeting lipid A biosynthesis, while revealing structural features of interest for future investigation of LpxD function. |
Databáze: | OpenAIRE |
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